JP5875660B2 - Anticancer drug side effect inhibitor and prognosis improving agent - Google Patents

Description

  The present invention relates to a side effect inhibitor of pharmacotherapy for colorectal cancer comprising fucoidan or a fucoidan-containing material. Specifically, drug therapy uses 5-fluorouracil, such as FOLFOX or FOLFIRI, and side effects are nausea, vomiting, fatigue, and the like. The present invention claims priority to Japanese Patent Application No. 2009-222553, the entire contents of which are incorporated herein by reference.

  Currently, anti-cancer drugs such as 5-fluorouracil (5-FU), oxaliplatin, CPT-11, and Avastin are used in various combinations for pharmacotherapy for colorectal cancer. In order for these anticancer agents to exert their effects, continuous use for a certain period is indispensable. However, when these anticancer agents are used, various side effects such as fatigue, leukopenia, and neurotoxicity appear in addition to gastrointestinal symptoms such as nausea, vomiting and diarrhea. For this reason, there are many cases in which continuation of anticancer agents has to be abandoned. In cases where the anticancer drug cannot be used continuously due to side effects, the effect of the anticancer drug cannot be exhibited, which is a great disadvantage for the patient. In other words, in cancer treatment, the side effects of anticancer agents are recognized as an urgent issue.

Fucoidan is a general term for sulfur-containing polysaccharides with fucose as the main chain, which is abundant in seaweed such as mozuku and mekabu (spore leaves of seaweed), and is distributed as food. Recently, it has been proved that fucoidan suppresses the growth of gastric cancer cultured cells and reduces the toxicity of 5-FU, which is an anticancer agent, to normal cells (see JP 2004-75595 A). However, it has not been reported yet whether or not fucoidan can actually reduce the toxicity of anticancer drugs in clinical practice.
JP 2004-75595 A

  It was a problem to be solved by the present invention to verify whether fucoidan can actually suppress the side effects of pharmacotherapy for colorectal cancer in clinical practice and to use fucoidan for such purposes.

  The inventors of the present invention have made extensive studies to solve the above problems, and found that fucoidan suppresses side effects such as nausea, vomiting and fatigue in colorectal cancer drug therapy using 5-FU. It came to be completed.

That is, the present invention provides the following.
(1) A side effect inhibitor of pharmacotherapy for colorectal cancer using 5-fluorouracil, comprising fucoidan or a fucoidan-containing material;
(2) The drug therapy is FOLFOX and / or FOLFIRI (1)
The side effect inhibitor described;
(3) The side effect inhibitor according to (1) or (2), wherein the side effect is a digestive system side effect and / or fatigue.
(4) The side effect inhibitor according to any one of (1) to (3), wherein fucoidan is derived from mozuku, or the fucoidan-containing material is mozuku;
(5) A method for inhibiting side effects of pharmacotherapy for colorectal cancer using 5-fluorouracil, comprising administering fucoidan or a fucoidan-containing material to a colorectal cancer patient;
(6) The method according to (5), wherein the drug therapy is FOLFOX and / or FOLFIRI;
(7) The method according to (5) or (6), wherein the side effect is a digestive system side effect and / or fatigue.
(8) The method according to any one of (5) to (7), wherein fucoidan is derived from mozuku, or the fucoidan-containing material is mozuku;
(9) Use of fucoidan or a fucoidan-containing material for the manufacture of a side effect inhibitor of pharmacotherapy for colorectal cancer using 5-fluorouracil;
(10) The use according to (9), wherein the drug therapy is FOLFOX and / or FOLFIRI;
(11) The use according to (9) or (10), wherein the side effect is a digestive system side effect and / or fatigue.
(12) The use according to any one of (9) to (11), wherein about 3 to about 5 g (dry weight) of fucoidan is administered per day by the side effect inhibitor;
(13) The use according to any one of (9) to (12), wherein the molecular weight of fucoidan is about 300,000;
(14) Use according to any one of (9) to (13), wherein fucoidan is derived from mozuku, or fucoidan-containing material is mozuku;
(15) The drug therapy is FOLFOX and / or FOLFIRI, and the side effect is one or more selected from the group consisting of fatigue, decreased appetite, nausea and vomiting, and The fucoidan is administered in an amount of about 0.5 to about 5 g (dry weight) per day, the fucoidan has a molecular weight of about 300,000, the fucoidan is derived from mozuku, or the fucoidan-containing material is mozuku. Use of any one of -14.
Furthermore, the present invention provides the following.
(16) An agent for improving the prognosis of pharmacotherapy for colorectal cancer using 5-fluorouracil, comprising fucoidan or a fucoidan-containing material;
(17) A method for improving the prognosis of pharmacotherapy for colorectal cancer using 5-fluorouracil, comprising administering fucoidan or a fucoidan-containing material to a colorectal cancer patient;
(18) Use of fucoidan or a fucoidan-containing material for the production of a prognosis improving agent for pharmacotherapy of colorectal cancer using 5-fluorouracil.

  ADVANTAGE OF THE INVENTION According to this invention, the side effect by the pharmacotherapy of colon cancer can be suppressed, the therapeutic effect with respect to a patient increases, and a patient's QOL is also raised.

FIG. 1 is a scheme illustrating the mFOLFOX6 therapy performed in Example 1. FIG. 2 is a graph comparing administration courses in the fucoidan administration group and the non-administration group. FIG. 3 is a graph comparing the survival rates of the fucoidan administration group (solid line) and the non-administration group (dashed line).

  The present invention provides a side effect inhibitor for cancer drug therapy comprising fucoidan or a fucoidan-containing material. Fucoidan is a sulfur-containing polysaccharide found in nature and is abundant in seaweed such as mozuku and mekabu. The fucoidan which is an active ingredient in the agent of the present invention may be a purified product or a crude product, for example, an extract from seaweed such as Mozuku.

  The fucoidan-containing material as an active ingredient in the agent of the present invention may be any material as long as it contains fucoidan and is non-toxic to humans. Preferred fucoidan-containing materials for the present invention include seaweeds, especially brown algae. Fucoidan-containing brown algae include mozuku (Okinawa mozuku, thread mozuku, taijikushi, stone mozuku, etc.), mekabu (squirt of wakame), wakame, arame, gagome, macomb, kurome, kajime, mitsuishikonbu, yoremoku, hijiki, Examples include, but are not limited to, Honda Walla, Yatsumata Moku, Akamoku, Hibamata, Umitorano. In the present specification, the term “mozuku” includes all types of mozuku, and particularly includes both Okinawa mozuku and yarn mozuku.

  The pharmacotherapy for colorectal cancer to which the agent of the present invention can be applied may be any pharmacotherapy as long as 5-fluorouracil (5-FU) is used. The drug therapy may be a drug therapy with 5-FU alone, or may be a drug therapy in combination with 5-FU and another drug. Examples of combinations of 5-FU and other drugs among colorectal cancer drugs currently widely used include FOLFOX and FOLFIRI, and modifications thereof, both of which are subject to application of the agent of the present invention. It is. FOLFOX is a drug therapy that uses 5-FU, folinic acid, and oxaliplatin in combination. FOLFOX includes FOLFOX4, FOLFOX6, modified FOLFOX6 (mFOLFOX6), FOLFOX7, and the like. FOLFIRI is a pharmacotherapy combining 5-FU, folinic acid and irinotecan. FOLFOX and FOLFIRI may be used alone or in combination. It is an application target of the agent of the present invention. The pharmacotherapy for colorectal cancer to which the agent of the present invention can be applied may be a combination of pharmacotherapy such as FOLFOX and FOLFORI with other pharmacotherapy such as Avastin. In the present specification, pharmacotherapy for colorectal cancer using a 5-FU prodrug such as capecitabine is also included in the pharmacotherapy using 5-FU.

  In the present invention, the colorectal cancer may be any kind, and includes cecal cancer, transverse colon cancer, ascending colon cancer, descending colon cancer, sigmoid colon cancer, rectal cancer and the like. In the present invention, colorectal cancer may be of any nature such as progressive or recurrent.

  The agent of the present invention is used in combination with pharmacotherapy for colorectal cancer. The agent of the present invention may be administered continuously from the start to the end of pharmacotherapy for colorectal cancer, or may be administered intermittently. The agent of the present invention may be administered before the start of colorectal cancer drug therapy, for example, several days ago, 2 weeks ago, 3 weeks ago, or 1 month ago. Further, the agent of the present invention may be administered after completion of colorectal cancer drug therapy to reduce remaining side effects. The agent of the present invention may be administered daily or may be administered at intervals of 1 to several days. The agent of the present invention may be administered once to several times a day, for example, 1 to 3 times. Usually, in the case of an adult, several tens mg to several g of fucoidan (in the case of a fucoidan-containing material, fucoidan dry weight can be administered) per day. For example, for adults, about 10 mg to about 10 g of fucoidan (dry weight) can be administered per day, such as about 10 mg to about 0.5 g, about 0.5 g to about 5 g, about 1 g to about 5 g. About 1 g to about 3 g, about 3 g to about 5 g, about 5 g to about 7 g, about 7 g to about 10 g of fucoidan (dry weight). Various conditions such as the administration timing, administration interval, administration route, dosage, and dosage form of the agent of the present invention are not limited to those described above, and the doctor can determine or change while watching the patient's condition and the degree of side effects it can.

  The administration route of the agent of the present invention is generally oral administration. In the case of oral administration, the agent of the present invention may be a solid dosage form such as powder, granule, tablet, capsule or the like, or a liquid dosage form such as solution, suspension or extract. Moreover, you may mix and administer the agent of this invention with food and drink. The agent of the present invention may be in the form of mozuku processed food. In addition to fucoidan or a fucoidan-containing material, the agent of the present invention may contain an excipient or carrier, or a flavor regulator such as vinegar, sugar, soy sauce, and flavor.

  The types of side effects of pharmacotherapy for colorectal cancer that are suppressed by the agent of the present invention are not particularly limited, but the agent of the present invention is particularly useful for digestive system side effects such as nausea and vomiting, and fatigue such as general malaise. Effective against one or more side effects selected from the group consisting of

  In a further aspect, the present invention provides a method for reducing side effects of pharmacotherapy for colorectal cancer, comprising administering to a patient a fucoidan or a fucoidan-containing material together with an anticancer agent. Preferably, the drug therapy is FOLFOX and / or FOLFIRI. Preferably, the side effect is one or more selected from the group consisting of fatigue, loss of appetite, nausea and vomiting. Preferably, the fucoidan is derived from mozuku or the fucoidan-containing material is mozuku.

  In a further aspect, the present invention provides the use of fucoidan or a fucoidan-containing material for the manufacture of a side effect inhibitor of pharmacotherapy for colorectal cancer. Preferably, the drug therapy is FOLFOX and / or FOLFIRI. Preferably, the side effect is one or more selected from the group consisting of fatigue, loss of appetite, nausea and vomiting. Preferably, the fucoidan is derived from mozuku or the fucoidan-containing material is mozuku.

  Reducing the side effects in pharmacotherapy for colorectal cancer increases the number of pharmacotherapy cools, increases the therapeutic effect, and improves patient survival and QOL. The number of anticancer drug administrations (cool number) for colorectal cancer using FOLFOX or FOLFIRI is set to be 10 or more. The fact that the number of cools of 10 or more can be achieved by the present invention shows a particularly remarkable effect of the present invention.

  In a further aspect, the present invention provides a prognosis improving agent for colorectal cancer pharmacotherapy using 5-fluorouracil, comprising fucoidan or a fucoidan-containing material; and administering fucoidan or a fucoidan-containing material to a colon cancer patient. A method for improving the prognosis of pharmacotherapy for colorectal cancer using fluorouracil; and the use of fucoidan or a fucoidan-containing material for producing a prognosis improving agent for pharmacotherapy of colorectal cancer using 5-fluorouracil

  The present invention will be described in more detail and specifically with reference to the following examples, but the examples are not intended to limit the present invention.

  Patients with advanced or recurrent colorectal cancer who are hospitalized or outpatient at Tottori University School of Medicine, who are scheduled to receive anticancer drug treatment (mFOLFOX6) (adult), or who are scheduled to receive mFOLFOX6 + Avastin treatment (adult) ) Was randomly divided into two groups, a fucoidan administration group (N = 10) and a non-administration group (N = 10). Prior to the study, these patients were outlined and the written consent was obtained.

The scheme for mFOLFOX6 therapy was as follows (see also Figure 1). The following dosing method and dosage were performed with 2 weeks as one course.
1) Administer 5-HT ₃ antagonist and steroid as pre-medication.
2) L-OHP (oxaliplatin) 85 mg / m2 is dissolved in 250 mL of 5% glucose solution.
3) Dissolve 200 mg / m2 of 1-LV (levofolinate) in 250 mL of 5% glucose solution.
4) Put 2) and 3) in separate bags and use the Y line, and simultaneously infuse over 2 hours.
5) Rapidly infuse 400 mg / m2 of 5-FU within 15 minutes.
6) Continuously inject 5-FU 2400 mg / m2 over 46 hours.
7) The oral steroid is administered for 3 days from the 2nd day of the treatment period.

  The fucoidan administration group contains a pack of seaweed food fucoidan (mozuku extract, seafood Kimuraya Co., Ltd.) (1 pack contains 1350 mg of fucoidan in dry weight, equivalent to 120 g of mozuku). Ingested 3 times a day. The administration period was 6 months from the start of anticancer drug treatment. The seaweed food fucoidan is prepared as follows. Okinawa mozuku (Cladosiphon okamuranus) was used as mozuku, suspended in water 1 to 5 times the moist weight of mozuku, and prepared acidic. Next, the mixture was heated to 50 ° C. or more to elute fucoidan, and then centrifuged to remove precipitates. The low molecular component was fractionated or dialyzed from the supernatant and concentrated and desalted to obtain fucoidan (mozuku extract). The low molecular fraction (fraction with a molecular weight of less than about 5000) was discarded. The weight average molecular weight (Mw) of the obtained fucoidan is about 300,000 in terms of molecular weight converted based on pullulan molecular weight (measured by gel filtration method: high-performance liquid chromatograph Prominence manufactured by Shimadzu Corporation and Showa Denko KK Column KS-805), and the sulfate group content was 13% based on the dry weight of fucoidan. Moreover, the yield of fucoidan from Okinawa mozuku wet weight 100 kg was 1.125 kg in dry weight.

The following items:
1. Loss of appetite; 2. Nausea, vomiting, 3. Diarrhea, 4. Stomatitis, 5. 5. neurological symptoms, 6. tiredness; The cytopenia was scored against the NCI-CTC criteria. Evaluation was performed every 3 months during the administration period. The number of patients that could be analyzed in the above study was 9 in the fucoidan administration group and 8 in the fucoidan non-administration group.

Table 1 shows the result of comparison of the total score in light of the NCI-CTC standard between the fucoidan administration group and the fucoidan non-administration group.

  In the fucoidan administration group, the reduction of fatigue was remarkable. Reduction of nausea and vomiting was also confirmed in the fucoidan administration group.

Table 2 summarizes the number of cases with more than moderate (2 points of NCI-CTC criteria).

  Fucoidan administration has been confirmed to be effective in reducing fatigue, moderate appetite, and decreased appetite, nausea and vomiting.

  Treatment was continued under the above test conditions, and the number of administrations of anticancer drugs (cooling of administration) was compared between the fucoidan administration group and the non-administration group (FIG. 2). In the fucoidan non-administered group, the average number of cools was 7.9 (SE 2.7), whereas in the fucoidan-administered group, the average number of cools was 13.8 (SE 0.3). The number of cools can be increased.

  Furthermore, the survival rate under the above test conditions was also examined (FIG. 3). The survival rate was tested by a log-rank test by the Kaplan-Meier method. In the fucoidan administration group, an improvement in survival rate was confirmed as compared to the fucoidan non-administration group.

  Based on the above results, fucoidan is effective in reducing side effects such as nausea, vomiting and other gastrointestinal side effects and fatigue associated with drug therapy including 5-FU such as FOLFOX and FOLFIRI in colorectal cancer cases. The number of treatments can be increased and the prognosis is also good.

  The present invention can be used in the pharmaceutical industry, the food manufacturing industry, and the like.

Claims (2)

Comprising fucoidan or a fucoidan-containing material, 5-fluorouracil a side effect inhibitor of drug therapy for colorectal cancer using, side effects moderate all SANYO or more (two points NCI-CTC criteria), fucoidan derived Mozuku Or a fucoidan-containing material, the fucoidan has a molecular weight of 300,000, and the side effect is a gastrointestinal side effect and / or fatigue (except for food aspects) . A prognostic agent for colorectal cancer pharmacotherapy using 5-fluorouracil containing fucoidan or a fucoidan-containing material , wherein fucoidan is derived from mozuku, or fucoidan-containing material is mozuku, and fucoidan has a molecular weight of 300,000. Prognostic improver (excluding food aspects) .